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Title Clinical characteristics of pleomorphic carcinoma of the lung

Author(s) Ito, Kenichiro; Oizumi, Satoshi; Fukumoto, Shinichi; Harada, Masao; Ishida, Takashi; Fujita, Yuka; Harada, Toshiyuki;Kojima, Tetsuya; Yokouchi, Hiroshi; Nishimura, Masaharu; Hokkaido Lung Cancer Clinical Study Group

Citation Lung Cancer, 68(2), 204-210https://doi.org/10.1016/j.lungcan.2009.06.002

Issue Date 2010-05

Doc URL http://hdl.handle.net/2115/43068

Type article (author version)

File Information LC68-2_204-210.pdf

Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP

https://eprints.lib.hokudai.ac.jp/dspace/about.en.jsp

1

Clinical Characteristics of Pleomorphic Carcinoma of the Lung

Kenichiro Ito a, Satoshi Oizumi a, Shinichi Fukumoto b, Masao Harada b, Takashi

Ishida c, Yuka Fujita d, Toshiyuki Harada e, Tetsuya Kojima f, Hiroshi Yokouchi g,

Masaharu Nishimura a, Hokkaido Lung Cancer Clinical Study Group

a First Department of Medicine, Hokkaido University School of Medicine,

Sapporo, Japan

b Department of Pulmonary Diseases, National Hospital Organization Hokkaido

Cancer Center, Sapporo, Japan

c Department of Pulmonary Medicine, Fukushima Medical University School of

Medicine, Fukushima, Japan

d Department of Respiratory Medicine, National Hospital Organization Dohoku

National Hospital, Asahikawa, Japan

e Section of Respiratory Diseases, Department of Internal Medicine, Hokkaido

Social Insurance Hospital, Sapporo, Japan

f Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo,

Japan

g Department of Medicine, Hokkaido Chuo Rosai Hospital, Iwamizawa, Japan

2

Correspondence to:

Satoshi Oizumi, First Department of Medicine, Hokkaido University School of

Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. Phone:

+81-11-706-5911; Fax: +81-11-706-7899; E-mail: soizumi@med.hokudai.ac.jp

ABSTRACT

Background: Pleomorphic carcinoma of the lung is a malignant epithelial tumor

that contains carcinomatous and sarcomatoid components. Due to its rarity,

few studies have been reported, and its clinical and pathological characteristics

remain unclear.

Method: We retrospectively investigated 22 cases of pleomorphic carcinoma of

the lung.

Results: Fifteen cases were diagnosed by surgical resection, four by autopsy,

and three by transbronchial biopsy. Nineteen patients were male and three

were female, and their mean age at diagnosis was 68.3 years (± 10.1).

Eighteen were current- or ex-smokers with substantial smoking histories (mean

46.4 pack-years). Sixteen patients had symptoms: hemoptysis and cough were

commonly seen. Chest computed tomography (CT) findings revealed that the

tumors were quite large (mean diameter 45.3 ± 21.9 mm; range 14-110 mm),

and 21 tumors were peripherally located. Positron emission tomography with

18-fluorodeoxy-glucose (FDG-PET) was performed in 12 patients, and the

Standardized Uptake Value (SUV) tended to be high (9.44 ± 4.98). In the 15

patients who underwent surgical resection, recurrence was common; systemic

metastases were also frequently found. Patients who had received surgical

mailto:kyamazak@med.hokudai.ac.jp�

3

treatment with proper follow-up care survived longer than those who did not

undergo surgery. Responses to chemotherapy were generally poor, although

one patient exhibited partial response to gefitinib.

Conclusions: Pulmonary pleomorphic carcinoma has strong malignant potential

with frequent distant metastases, as has already been reported. However, this

study demonstrated that surgical treatment and appropriate follow-up therapy

might result in better prognoses.

Keywords: pleomorphic carcinoma; FDG-PET; surgery; chemotherapy; gefitinib;

prognosis

4

1. Introduction

According to the World Health Organization classification of lung tumors,

pleomorphic carcinoma of the lung is one of five subgroups of sarcomatoid

carcinoma [1], which itself is defined as a group of poorly differentiated tumors

characterized pathologically by a combination of epithelial and mesenchymal

elements. Pleomorphic carcinoma is histologically defined as either non-small

cell carcinoma combined with neoplastic spindle and/or giant cell or a carcinoma

that consists of only spindle cell and giant cell. At least 10% of the neoplasm

should be pleomorphic.

If the tumor consists of only spindle cells or only giant cells, it is defined as a

spindle cell or giant cell carcinoma, which are other subgroups of sarcomatoid

carcinoma. Carcinosarcoma, which contains carcinoma and sarcoma, is

another subgroup. Sarcoma components differentiate to osteosarcoma,

chondrosarcoma, and rhabdomyosarcoma. Bone, cartilage, muscle, fat, and

neuron are sometimes detected pathologically in tumors. Pulmonary blastoma

is a very rare type of sarcomatoid carcinoma characterized as biphasic tumor

containing a primitive epithelial component resembling well-differentiated

fetal-type adenocarcinoma and a primary mesenchymal stroma.

Since its diagnostic criteria were confirmed, pulmonary pleomorphic

carcinoma has been diagnosed more frequently. It is essential to understand

its clinical behavior for effective management of patients with this disease.

However, as pulmonary pleomorphic carcinoma is rare (only 0.1-0.4% of all

malignant tumors of the lung) [2-4], its clinical and pathological characteristics

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are not well known. We have retrospectively investigated 22 patients with

pulmonary pleomorphic carcinoma diagnosed by surgical resection, autopsy, or

transbronchial biopsy (TBB). Radiological findings, results of positron emission

tomography with 18-fluorodeoxy-glucose (FDG-PET), treatment, and clinical

course are described in this report.

2. Material and methods

2.1. Patients

We retrospectively analyzed 22 pulmonary pleomorphic carcinomas from a

total of 2447 primary lung cancers (including 1022 cases of resected lung

cancer) that we experienced between January 2005 and December 2008 at

seven institutes (Hokkaido University Hospital, National Hospital Organization

Hokkaido Cancer Center, Fukushima Medical University School of Medicine,

National Hospital Organization Dohoku National Hospital, Hokkaido Social

Insurance Hospital, Hokkaido Chuo Rosai Hospital, and KKR Sapporo Medical

Center). Pathological diagnosis was made by surgical resection, autopsy, or

TBB. The incidence of pulmonary pleomorphic carcinoma was 0.90%. This

study was approved by the institutional review boards of each institute, and all

patients provided written informed consent.

2.2. CT and FDG-PET protocol

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Chest computed tomography (CT) was performed in all patients. The size,

location, and internal density of the tumor, and the presence of a cavity were

evaluated. Hilar and mediastinal lymph nodes were measured, and if the

short-axis diameter of a lymph node was equal to or longer than 10 mm, it was

considered positive. Abdomen CT was also performed to detect metastases to

abdominal organs such as liver, kidney, and adrenal gland.

Positron emission tomography with 18-fluorodeoxy-glucose (FDG-PET) has

been used for evaluating tumors of the lung as well as lymph node and distant

metastases. The Standardized Uptake Value (SUV), which was obtained by

placing a region of interest over the lesion and dividing the value (in microcuries

per cubic centimeter) by the injected dose (in microcuries) divided by the

patient’s body weight (in grams) [5], was measured. In this series, 12 patients

underwent FDG-PET.

2.3. Pathological diagnosis

Pleomorphic carcinoma was defined as non-small cell carcinoma containing

at least 10% sarcomatoid components. Pathologists evaluated specimens that

were obtained by surgery, autopsy and TBB. In this study, when a TBB

specimen contained both carcinomatous and sarcomatoid components, and the

non-small cell lung cancer component was clearly distinct from the spindle/giant

cell carcinoma, the tumor was diagnosed as pleomorphic carcinoma.

2.4. Evaluation of response to chemotherapy or radiotherapy

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Response evaluations for chemotherapy and/or radiotherapy were assessed

using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines [6].

Overall survival was defined as the time from the first day of treatment until

death from any cause.

2.5. Statistical analysis

In this paper, statistical values are given as mean ± standard deviation.

Continuous variables were compared using the Student t test or Mann-Whitney

test, as appropriate. All survival curves for time-to-event variables were

created using the Kaplan-Meier method [7].

3. Results

3.1. Patient characteristics

Patient characteristics are summarized in Table 1. The male:female ratio

was 19:3. The age at diagnosis was 68.3 ± 10.1 years (range 51-94).

Symptoms were seen in 16 patients (72.7%): common symptoms were

hemoptysis (seven cases) and cough (six cases). Fever, pain, dyspnea and

body weight loss were also seen. Six patients (27.3%) had no symptoms but

were referred to hospital with lung nodules detected on chest X-rays. Eighteen

patients (81.8%) were current or ex-smokers, and the remaining four (18.2%)

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had never smoked. The smoking history was striking: the mean number of

pack-years of the 22 patients was 46.4 ± 36.3, with a maximum value of 160

pack-years (patient 5); the mean value of the 18 smokers was 56.7 ± 31.8

pack-years.

Biochemical examination revealed that in 14 of the 22 cases (63.6%), serum

carcinoembryonic antigen (CEA) was high, at 18.1 ± 41.2 ng/ml (normal 1.0 -

6.5). In 10 of the 18 cases examined (55.6%), cytokeratin fragment 19 (CYFRA

21-1) was also increased (4.0 ± 4.3 mg/ml; range 0.0 - 14.1; normal 0.0 - 2.0).

No other tumor markers examined, including carbohydrate antigen 19-9

(CA19-9), Sialyl Lewis (x) (SLX), squamous-cell carcinoma antigen (SCC-Ag),

pro-gastrin-releasing peptide (Pro-GRP), and neuron-specific enolase (NSE),

were specific and useful for diagnosis of pleomorphic carcinoma of the lung.

3.2. Radiological findings

Chest CT was performed in all 22 cases and revealed fairly large tumors:

45.3 ± 21.9 mm in diameter (range 14 - 110). All tumors were observed as

mass or nodule, and ground glass opacity pattern or consolidations were not

seen in our study. One case (patient 17) had a cavity inside the tumor (tumor

diameter 50 mm). Twenty-one tumors (95.5%) were located in the peripheral

field of the lung, while one was central (patient 20, non-small cell carcinoma +

spindle cell). In 15 cases (68.2%), the primary tumor was located in the upper

lobe (right: 12 cases; left: 3 cases), and the remaining seven tumors (31.8%)

were located in the middle or lower lobe. Four cases exhibited internal low

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densities and heterogeneous pattern (patients 1, 14, 15, and 19). At the time of

diagnosis, chest wall invasions were found in two patients (patients 6 and 17)

and clinical T4 disease (malignant pleural and/or pericardial effusion, pleural

dissemination, mediastinal invasion, and metastases to the same lobe) in four

patients (patients 14, 16, 19, and 22). Clinical nodal involvements on CT

findings were observed in 13 of the 22 patients (7 of 15 patients who underwent

surgical resection).

Twelve patients underwent FDG-PET, and the SUV of the primary lesions

tended to be high (9.44 ± 4.98; range 3.00 - 16.6). SUVs of T1 (≤ 3 cm) and T2

(> 3 cm) disease were 7.16 ± 4.59 and 9.89 ± 5.16, respectively. Most of the

metastatic lymph nodes and distant metastases also exhibited high SUV.

3.3. Diagnosis and pathological findings

Fifteen cases of pulmonary pleomorphic carcinoma were diagnosed by

surgical resection (Table 1; patients 1 – 15). Representative histological finding

of the resected tumor is shown in Fig. 1A (patient 4, squamous cell carcinoma

with spindle cell). Eleven of the 15 tumors were diagnosed as primary lung

cancer by sputum and/or transbronchial brushing cytology, or TBB before

surgery. Another four cases (Table 1; patients 16 – 19) were confirmed by

autopsy to have pulmonary pleomorphic carcinoma. In the other three patients

(Table 1; patients 20 – 22), sarcomatoid elements were successfully detected

with TBB (Fig. 1B, patient 21, large cell carcinoma with giant cell), and

pleomorphic carcinoma was diagnosed without surgical resection or autopsy.

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Sputum cytology was performed in 15 patients. In two patients (13.3%),

carcinoma cells but not sarcomatoid elements were detected: one case (patient

10) was diagnosed as squamous cell carcinoma and the other (patient 4) as

adenosquamous cell carcinoma.

Transbronchial brushing cytology and/or TBB was performed in 21 patients,

confirming 17 cases of lung cancer. In 7 of the 17 cases, sarcomatoid elements

were pathologically obtained in specimens. Three (patients 1, 9, and 11) of

these patients received surgical resection, and one (patient 18) underwent

autopsy. The other three (patients 20 – 22) patients were diagnosed with

pleomorphic carcinoma by the TBB results alone without surgery or autopsy.

We also investigated differences in clinical features according to pathological

subtypes. Large cell carcinoma combined with giant cell (six cases, 27.3%)

and adenocarcinoma combined with spindle cell (four cases, 18.2%) were

predominantly observed. We did not find any statistical differences in clinical

or radiological characteristics according to pathological subtypes.

3.4. Clinical course and prognosis for patients having surgical treatment

Clinical stages at the point of diagnosis were stage IA in four cases (18.2%),

stage IB in three cases (13.6%), stage IIB in four cases (18.2%), stage IIIA in

three cases (13.6%), stage IIIB in three cases (13.6%), and stage IV in five

cases (22.7%) (Table 1). Of the 15 patients with surgical resection (patients 1 –

15), pathological stage (p-stage) was upgraded compared with clinical stage

(c-stage) in four cases (26.7%). Pathological stages were stage IA in three

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cases (20%), stage IB in three cases (20%), stage IIB in four cases (26.7%),

stage IIIA in two cases (13.3%), stage IIIB in two cases (13.3%), and stage IV in

one case (6.7%) (Table 1). Fig. 2A shows overall Kaplan-Meier survival curve

in all of the enrolled 22 patients. Median survival time (MST) was 213 days.

Of the 15 patients who underwent surgery, six patients, including five with

pN0 disease, relapsed after surgery. Four of them had recurrence by distant

metastases (two to the brain, one to lung, and one to bone). Four of these

patients died from relapsed cancer, while two patients (patients 9 and 15) are still

alive (one of them is receiving gefitinib）. The other nine patients have not

developed any recurrence at the time of analysis, including two patients who

died of non-cancer-related disease (pneumonia and heart disease).

Four patients (patients 1, 6, 10, and 14) received adjuvant chemotherapy

post-surgery. Patient 6 exhibited pT3N0M0 (stage IIB) with chest wall invasion

and received chemo-radiation therapy (cisplatin plus docetaxel and 65 Gy

radiation in total). This patient was still alive without recurrence 441 days after

surgery. Other three patients received chemotherapy alone. Patient 1

received UFT (Tegafur/Uracil) and was alive without recurrence 573 days after

surgery. Patient 10 had adjuvant chemotherapy with vindesine, UFT, and

OK432. This patient had recurrence 78 days after surgery and died after 126

days. Patient 14 received carboplatin and gemcitabine and was alive 98 days

after surgery.

Patient 9 and 15 received chemotherapy for a recurrent tumor after surgery

(Table 2). Patient 9 received cisplatin plus docetaxel as first-line therapy, and

the response was stable disease (SD). It is noteworthy that the case (a

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70-year-old non-smoker woman) exhibited partial response to gefitinib as

second-line therapy. The pathological subtype of this case was

adenocarcinoma combined with spindle cell. Interestingly, the tumor harbored

epidermal growth factor receptor (EGFR) mutations (L858R).

Fig. 2B shows overall Kaplan-Meier survival curve in the 15 patients who

underwent surgical resection. Nine patients were still alive at the time of

analysis, and MST was not determined.

3.5. Clinical course and prognosis for patients who did not undergo surgery but

received chemotherapy or radiotherapy

Four (patients 16, 17, 19, and 21) of the seven cases who did not undergo

surgical resection (patients 16 – 22) and one (patient 15) of patients who

received surgery had distant metastases at the time of diagnosis (stage IV).

The metastasis sites were bone (two cases), lung, adrenal gland, skin, and

lymph node (one case each). Three patients (patients 18, 20, and 22) did not

have surgical treatment because they had c-stage IIIB disease (patients 18 and

22) or advanced age (patient 20; 94 years old). During their clinical course,

other metastases to brain, liver and the small intestine appeared. One patient

(patient 18) died of perforation of the small intestine because of metastasis.

Autopsy (patients 16 － 19) revealed small metastases to heart, kidney, thyroid

gland and distant lymph nodes that could not be proven by CT or MRI before

death. Fig. 2B shows Kaplan-Meier overall survival curve for the seven patients

who did not undergo surgery; MST was 118 days.

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Three patients received chemotherapy against advanced tumor without

surgical resection (patients 17, 18, and 19). As first-line therapy, the patients

received carboplatin plus paclitaxel (patients 17 and 18) and carboplatin plus

docetaxel (patient 19). Two received gemcitabine plus vinorelbine as

second-line treatment (patients 17 and 18). Only patient 17 received gefitinib

as third-line and TS-1 as fourth-line treatments. Response was very poor, as

shown in Table 2 (there were two NE (Not Evaluated) cases because of

difficulties in performing follow-up examinations after onset of acute

drug-induced pneumonitis). Even with first-line chemotherapy, no partial

response was observed with the cytotoxic agents. The MST of these three

patients (who did not undergo surgical treatment) was 213 days.

A total of six patients received irradiation for primary tumor causing back pain

(patient 22), for brain metastasis (patient 8), for bone metastasis (patients 9 and

21), and as adjuvant therapy after surgical resection for pT3 tumors (patients 6

and 7).

Two of twenty-two patients received best supportive care because of

advanced age and poor Eastern Cooperative Oncology Group Performance

Status (ECOG PS) (patients 16 and 20).

4. Discussion

Lung tumors have been reclassified by the World Health Organization. In

1999, a group named “carcinoma with pleomorphic, sarcomatoid, or

sarcomatous elements” was defined. In 2004, this group, which contained

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pleomorphic carcinoma, was renamed “Sarcomatoid carcinoma” [1]. Travis

WD et al. had previously reported pleomorphic carcinoma of the lung to be very

rare (approximately 0.1 - 0.4% of all lung malignancies) [2-4]. Since its

pathological definition became widely recognized, pleomorphic carcinoma has

been diagnosed more frequently: in our study, its frequency was 0.90% (22/2447

cases). In another recent study, it was found to be 1.6% (45/2743) of resected

non-small cell lung cancer (NSCLC) [8]. As in previous reports [8-12], most

cases in our study were male with a history of smoking; they exhibited symptoms

such as hemoptysis and cough.

Pleomorphic carcinoma of the lung was often found as a large mass, more

than 4 – 5 cm in diameter. In our study, the tumors tended to be located in the

periphery of the upper lobes. Frequently observed hemoptysis might be

characteristic of pulmonary pleomorphic carcinoma in spite of its peripheral

location. We discovered sarcomatoid elements in seven cases by

transbronchial brushing cytology and/or biopsy; however, there were no cases

diagnosed only with cytological examination. Even when the component is

included in the specimen, definite diagnosis of pleomorphic carcinoma should be

avoided because it is difficult to differentiate the spindle component from active

fibroblasts, as well as a giant cell component from multinucleated histiocytes.

Kim et al. reported that 86% of pulmonary pleomorphic carcinomas with an

adenocarcinoma component and 100% of those with a large cell carcinoma

component were located in the periphery, while 100% of the pleomorphic

carcinomas with a squamous cell carcinoma component were located in the

central region [10]. They also demonstrated that the CT features of the tumor

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appeared to be dictated by its epithelial components. However, in our study,

only one tumor was centrally located, the subtype of which was non-small cell

carcinoma combined with spindle cell. All three cases of pulmonary

pleomorphic carcinomas with a squamous cell carcinoma component were

located in the periphery. In addition, CT features such as a cavity and

heterogeneous density in the tumor that reflected necrosis or hemorrhage were

not related to tumor subtypes. Neither patient characteristics (age, sex,

smoking history, and symptoms), FDG-PET findings, response to chemotherapy,

nor prognosis differed significantly between pathological subtypes. Mochizuki

et al. also described that there were no significant differences in the overall

survival between groups divided by predominant epithelial component [12].

FDG-PET was useful in examining patients with pleomorphic carcinoma of

the lung, because it showed higher SUV in primary lesions even if the size of the

tumor was small (minimum size was 15 mm in the 12 examined cases). SUVs

of T1 (≤ 3 cm) and T2 -4 (> 3 cm) disease were 7.16 ± 4.59 and 9.89 ± 5.16,

respectively. Tournoy et al. has reported mean SUVs of T1 and T2-4 NSCLC

as 3.71 and 5.20 [13]. There was a statistically significant difference in SUV of

T2-4 diseases between NSCLC and pleomorphic carcinoma (P < 0.01), whereas

there was no significant difference in SUV of T1 diseases (P = 0.48). Although

there were only two T1 tumors in our study, our FDG-PET result suggests that

the SUV of pleomorphic carcinoma might be higher than that of common

non-small cell lung cancer, which might be helpful in diagnosis.

Biochemical examination revealed serum CEA to be elevated in 63.6% of

patients (14 cases). This marker is known to be specific for other tumors

16

including adenocarcinoma and is affected by external factors such as smoking.

SCC, CYFRA, SLX, Pro-GRP, and NSE were considered to be non-specific

markers for pulmonary pleomorphic carcinoma.

Distant metastasis was frequently observed in patients with pleomorphic

carcinoma of the lung. The major sites of distant metastases were the same as

those for other malignant epithelial lung tumors, i.e., bone, brain, lung, liver and

adrenal gland, but the progression of this tumor is particularly rapid, and distant

metastases seem to strongly influence prognosis. Autopsies revealed that

pleomorphic carcinomas of the lung tended to expand into various lesions: minor

sites of metastases such as thyroid grand, peritoneum and lymph nodes of

abdomen could not be found by clinical examination before death. In particular,

metastases to small intestine were revealed by autopsy in two patients, one of

whose death (patient 18) was a result of intestine perforation.

Chest wall invasions and mediastinal invasions were commonly observed in

the 15 patients who underwent surgical resection, as postoperative pathological

findings rather than preoperative prediction. Because of pT3 disease, three

cases were given adjuvant therapy (irradiation (patient 7) or chemotherapy

(patient 1) or chemo-radiation therapy (patient 6)). Recurrence after surgery

was frequently observed, and it should be noted that five cases with pN0

disease also relapsed. While Raveglia et al. reported that nodal involvement

was a determinant prognostic variable of pleomorphic carcinoma of the lung [9],

Yuki et al. commented that even patients with pN0 disease frequently

experienced vascular invasion (57.1%) [8]. We have to keep in mind that

pleomorphic carcinoma of the lung has the potential to recur even if the primary

17

lesion is resected at an early stage. In our study, the 15 patients who

underwent surgery better prognoses, with nine patients surviving, compared with

a MST of 118 days for patients who had not received surgery. One reason

might be that some patients properly received chemotherapy, irradiation, or

combination as adjuvant therapy post-surgery or when the relapsed tumor was

found; indeed four patients receiving the treatments are still alive.

Chemotherapy was administered to nine patients, four of whom received

adjuvant chemotherapy after surgery, while the other five had recurrence after

surgery or advanced cases without surgery; however, neither platinum-based

nor non-platinum-based chemotherapy was effective. Bae et al. also

commented that advanced pulmonary pleomorphic carcinoma showed poor

response to chemotherapy regimens [11]. Of note is the fact that we

experienced one partial response to gefitinib despite this being second-line

treatment (patient 9). The tumor in this case was diagnosed as pleomorphic

carcinoma by surgical resection, and EGFR mutation (L858R) was detected.

The presence of EGFR mutation is related to a patient’s background and

pathological subtypes of the lung cancer: it influences response to gefitinib [14].

This Japanese patient was female with no history of smoking, and the subtype of

the tumor was adenocarcinoma combined with spindle cell. She had relapsed

19 months after surgery. First, she received platinum-based chemotherapy,

which caused a SD response, and then gefitinib as second-line treatment

resulted in survival for 890 days after surgery. It was not clear whether gefitinib

was effective for only the adenocarcinoma component and not the spindle cell

component since we could not obtain a tumor tissue sample after treatment.

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However, the good response to second-line gefitinib highlighted the importance

of molecular targeted therapy for this entity.

5. Conclusion

In conclusion, we retrospectively analyzed 22 cases of pulmonary

pleomorphic carcinoma in a total of 2447 cases of primary lung cancer.

Pulmonary pleomorphic carcinoma had strong malignant potential with frequent

distant metastases. We demonstrated that surgical treatment and appropriate

follow-up therapy including the use of a molecular targeting drug (e.g., gefitinib

for patients with adenocarcinoma as carcinomatous component) might improve

outcomes. Some other important findings regarding the characteristics and

clinical course of the tumor have been described in this report, and further

investigations will be needed to elucidate more definitive clinical features and to

establish appropriate methodological strategies for pleomorphic carcinoma of

the lung.

Acknowledgements

We are grateful to Dr Koichi Yamazaki, former associate professor of the First

Department of Medicine, Hokkaido University School of Medicine, for his

outstanding support. We also thank Dr Yoshihiro Matsuno (Hokkaido University

Hospital), Dr Katsushige Yamashiro (Hokkaido Cancer Center), Dr Kazuo

Watanabe (Fukushima Medical University Hospital), Dr Yuichiro Fukasawa (KKR

19

Sapporo Medical Center), and Dr Kenzo Okamoto (Hokkaido Chuo Rosai

Hospital), for valuable assistance in pathological diagnosis and review.

20

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FIGURE LEGENDS

Figure 1. Histological findings of pleomorphic carcinoma. (A) A spindle cell

carcinoma component seen in a surgically resected tumor (Patient 4,

hematoxylin and eosin, × 100). (B) A giant cell carcinoma component in a

tumor tissue obtained by transbronchial biopsy (Patient 21, hematoxylin and

eosin, × 100).

Figure 2. (A) Kaplan-Meier overall survival of all patients and (B) overall survival

of patients treated with surgery (15 patients) or without surgery (7 patients).

1

TABLE 1.Clinical and pathological findings of 22 patients with pleomorphic carcinoma of the lung.Patient Sex Age Smoking Symptoms CEA Pathological subtypes c-Stage p-Stage

No. (years) history (ng/ml) Carcinomatous component Sarcomatoid component(pack-years)

Surgical resection1 M 79 75 hemoptysis 7.7 Large cell carcinoma Giant cell cT2N1M0 IIB pT3N2M0 IIIA

body weight loss2 M 67 42 none 12.4 Adenocarcinoma Giant cell cT1N0M0 IA pT1N0M0 IA

3 M 70 37.5 fever 8.8 Large cell carcinoma Giant cell cT2N1M0 IIB pT2N0M0 IB

4 M 77 35.6 hemoptysis 8.1 Squamous cell carcinoma Spindle cell cT2N2M0 IIIA pT4N2M0 IIIB

5 M 77 160 none 9.8 Large cell carcinoma Spindle cell cT2N1M0 IIB pT2N1M0 IIB

6 M 59 51.3 none 6.6 Adenosquamous cell carcinoma Spindle cell cT3N0M0 IIB pT3N0M0 IIB

7 M 64 66 hemoptysis 2.3 Adenocarcinoma Spindle cell cT2N0M0 IB pT3N0M0 IIBcough

8 M 64 67.5 hemoptysis 7.5 Adenocarcinoma Spindle cell cT2N0M0 IB pT2N0M0 IB

9 F 70 0 cough 12.8 Adenocarcinoma Spindle cell cT1N0M0 IA pT1N0M0 IA

10 M 73 31.8 hemoptysis 8.3 Squamous cell carcinoma Spindle cell + Giant cell cT2N2M0 IIIA pT2N2M0 IIIA

11 M 71 56 dyspnea 3.4 Adenocarcinoma Giant cell cT2N2M0 IIIA pT2N1M0 IIB

12 M 74 50 hemoptysis 2.8 Large cell carcinoma Giant cell cT2N0M0 IB pT2N0M0 IB

13 M 68 55 none 1.3 Large cell carcinoma Giant cell cT1N0M0 IA pT1N0M0 IA

14 M 51 33.8 dyspnea 0.7 Non-small cell carcinoma Giant cell cT4N0M0 IIIB pT4N0M0 IIIBcough

15 M 54 82.5 none 2.7 Adenocarcinoma Giant cell cT2N2M1 IV pT4N0M1 IV

Autopsy16 M 73 75 dyspnea 197 Large cell carcinoma Spindle cell + Giant cell cT4N3M1 IV

back pain17 M 52 30 hemoptysis 37.2 Squamous cell carcinoma Spindle cell + Giant cell cT3N2M1 IV

cough18 M 57 60 cough, sputum 15.4 Large cell carcinoma Giant cell cT2N3M0 IIIB

fever19 F 63 0 cough, fever 4.4 Adenocarcinoma Giant cell cT4N1M1 IV

TBB (transbronchial biopsy)20 M 94 0 none 8.1 Non-small cell carcinoma Spindle cell cT1N0M0 IA

21 F 70 0 none 38.4 Large cell carcinoma Giant cell cT2N3M1 IV

22 M 76 12.5 back pain 2.9 Adenocarcinoma Spindle cell cT4N2M0 IIIB

CEA: carcinoembryonic antigen

2

TABLE 2.Summary of chemotherapy for 5 patients except for adjuvant therapy.Patient No. Situation Stage Regimens （Best Response）

9 recurrence after surgery pT1N0M0 IA CDDP/DOC （SD） → Gef （PR）

15 recurrence after surgery pT4N0M1 IV CBDCA/PTX （SD）

17 no indication of surgery cT3N2M1 IV CBDCA/PTX （SD） → GEM/VNR （PD） → Gef （NE*） → S-1 （PD）

18 no indication of surgery cT2N3M0 IIIB CBDCA/PTX （SD） → GEM/VNR （NE*）

19 no indication of surgery cT4N1M1 IV CBDCA/DOC （SD）

*occurred drug-induced interstitial pneumonitisCDDP: cisplatin, DOC: docetaxel, Gef: gefitinib, CBDCA: carboplatin, PTX: paclitaxel, GEM: gemcitabine, VNR: vinorelbine,S-1: TS-1, PR: partial response, SD: stable disease, PD: progressive disease, NE: not evaluated

Clinical Characteristics of Pleomorphic Carcinoma of the Lung